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RET/PTC Rearrangements Preferentially Occurred in Papillary Thyroid Cancer among Atomic Bomb Survivors Exposed to High Radiation Dose

Departments of ¹ Radiobiology/Molecular Epidemiology, ² Statistics, and ³ Epidemiology (Nagasaki), Radiation Effects Research Foundation, ⁴ Department of Pathology, Hiroshima University Hospital, ⁵ Department of Pathology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, ⁶ Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, and ⁷ Geriatric Health Service Facility Hidamari, Hiroshima, Japan; ⁸ Translational Research Center, Saitama University, International Medical Center, Saitama, Japan; and ⁹ Department of Pathology, Nagasaki University Hospital, and ¹⁰ Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Requests for reprints: Kiyohiro Hamatani, Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima-shi, Hiroshima 732-0815, Japan. Phone: 81-82-261-3169; Fax: 81-82-261-3170; E-mail: hamatani{at}rerf.or.jp.

Key Words: RET rearrangement • BRAF^V600E mutation • radiation dose • time after exposure • radiation-associated thyroid carcinogenesis

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF^V600E point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF^V600E mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P_trend = 0.002). In contrast, BRAF^V600E mutation was less frequent in cases exposed to higher radiation dose (P_trend < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF^V600E mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis. [Cancer Res 2008;68(17):7176–82]